Neuronal cells are highly sensitive to proteo-toxicity and neurodegenerative diseases such as Huntington's, Alzheimer's, Parkinson's and prion-based disease are associated with the presence of inappropriately folded or aggregated proteins. Protein chaperones function in the proper folding, processing and turnover of proteins and serve to protect cells from proteo-toxicity. Experimental evidence in cellular and animal models of neurodegenerative diseases associated with protein misfolding strongly support a potential therapeutic role for elevated protein chaperone expression. The human Heat Shock Transcription Factor 1 (HSF1) coordinately activates both basal and inducible expression of many genes encoding protein chaperones and other proteins that protect cells from stress and cell death, suggesting that HSF1 is an attractive target for pharmacological intervention in neurodegenerative disease. In this application I outline two specific aims that focus on the characterization of novel small molecules and regulatory proteins that could provide a basis for pharmacological intervention to enhance protein chaperone expression. In the first Specific Aim I outline experiments to understand the detailed mechanism of action of a novel small molecule, HSF1A, capable of coordinately inducing protein chaperone expression through the activation of human HSF1. In the second Specific Aim I outline experiments to evaluate the function of HSF1A, and structurally related molecules, in striatal cell culture, a corticostriatal rat brain slice model of Huntington<s disease and in a fruit fly model of neurodegenerative disease associated with polyQ protein aggregation. These studies will provide critical mechanistic information on novel small molecules as potential therapeutic approaches to coordinately elevate protein chaperone expression and to ameliorate protein aggregation defects associated with Huntington<s disease and other human neurodegenerative diseases of protein misfolding.